Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

Julien N. Bianco, Valérie Bergoglio, Yea-Lih Lin, Marie-Jeanne Pillaire, Anne-Lyne Schmitz, Julia Gilhodes, Amelie Lusque, Julien Mazières, Magali Lacroix-Triki, Theodoros I. Roumeliotis, Jyoti Choudhary, Jérôme Moreaux, Jean-Sébastien Hoffmann, Hélène Tourrière () and Philippe Pasero ()
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Julien N. Bianco: CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer
Valérie Bergoglio: University of Toulouse 3
Yea-Lih Lin: CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer
Marie-Jeanne Pillaire: University of Toulouse 3
Anne-Lyne Schmitz: CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer
Julia Gilhodes: Institute Universitaire du Cancer Toulouse-Oncopole (IUCT-O)
Amelie Lusque: Institute Universitaire du Cancer Toulouse-Oncopole (IUCT-O)
Julien Mazières: Toulouse University Hospital, University Paul Sabatier
Magali Lacroix-Triki: Gustave Roussy Cancer Campus
Theodoros I. Roumeliotis: The Institute of Cancer Research
Jyoti Choudhary: The Institute of Cancer Research
Jérôme Moreaux: CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer
Jean-Sébastien Hoffmann: University of Toulouse 3
Hélène Tourrière: CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer
Philippe Pasero: CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.

Date: 2019
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DOI: 10.1038/s41467-019-08886-8

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